Is treatment with ritonavir a risk factor for myocardial infarction in HIV-infected patients?

In comparison with healthy controls, decreased levels of total, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol have been observed during the entire course of HIV infection, whereas serum triglycerides tend to be elevated during advanced HIV infection and AIDS [1–3]. Increased frequency of asymptomatic atherosclerosis has also been reported in HIV-infected subjects, possibly due to decreased HDL cholesterol [4]. Ritonavir exhibits documented efficacy against HIV infection [5,6]. Amongst the known adverse effects induced by ritonavir is reversible hyperlipidaemia, with increases of triglycerides by 200–300% and cholesterol by 30–40% [5]. In some patients, however, the increases in both triglycerides and cholesterol can be much more dramatic [7]. We report here an AIDS patient whose blood lipids changed severely during treatment with ritonavir combined with zidovudine and lamivudine, and who unexpectedly suffered an acute myocardial infarction 15 months after triple therapy had been instituted. The patient, a lean, 175 cm tall, 41-year-old homosexual man, was initially diagnosed with HIV infection in 1988. He suffered his first AIDS-defining illness in July 1996 when he developed progressive cutaneous Kaposi's sarcoma, which was treated with liposomal doxorubicin (13 infusions of 40 mg every 3–4 weeks). Due to a partial response of Kaposi's sarcoma, this treatment was subsequently stopped in August 1997. In July 1996, prophylaxis with trimethoprim-sulphamethoxazole and antiretroviral therapy were initiated, combining zidovudine 250 mg twice daily, lamivudine 150 mg twice daily, and ritonavir 600 mg twice daily. Before therapy started, CD4 lymphocytes were 226 × 106/l (10% of total lymphocytes) and HIV RNA was 83 346 copies/ml plasma, with normal values for haematology and blood chemistry. Antiretroviral therapy was well tolerated and was continued without changes until November 1997. In November 1997, the patient suffered an acute inferoposterior myocardial infarction complicated initially by severe right ventricular failure. No thrombolytic therapy was established because he was admitted 13 h after the onset of pain. Echocardiography demonstrated an akinetic right ventricle and severe tricuspid regurgitation. Coronary angiography was carried out, documenting a long-range thrombotic occlusion of the right coronary artery and irregular wall thickenings of the left anterior descending and left circumflex coronary arteries. Reperfusion of the right coronary artery was accomplished by coronary angioplasty and the signs of right ventricular failure slowly regressed. The assessment of risk factors revealed cigarette smoking (30 pack-years), high total cholesterol, low HDL cholesterol, and hypertriglyceridaemia. Diabetes mellitus was excluded by normal haemoglobin A1c and normal glucose tolerance test. There was no family history of atherosclerosis. Although the cholesterol levels were already slightly abnormal in July 1996, before any medication was taken, the blood lipids became highly abnormal only after antiretroviral therapy started; 2.5 months before the infarction, total cholesterol was 10.3 mmol/l and fasting triglycerides were 7.1 mmol/l (Table 1). After the infarction, ritonavir was replaced by nelfinavir, and fluvastatin was additionally instituted, which led to normalization of triglycerides and partial reversal of the abnormal levels of total and HDL cholesterol.Table 1: . Time course of body weight and laboratory valuesThe changes in blood lipids that occurred were most likely due to ritonavir, as suggested by the time course of the lipid values in relation to antiretroviral therapy. The mechanism by which the drug alters lipid levels is not known. It is possible that ritonavir may decrease the clearance of lipoproteins or may enhance lipid synthesis by influencing hepatic enzyme synthesis. Due to the lack of long-term studies, the clinical significance of ritonavir-induced dyslipidaemia has yet to be determined. Our patient suffered an atherosclerotic occlusion of the right coronary artery. Even in a moderate smoker, such an event with consecutive myocardial infarction is unexpected at the age of 41 years and an aetiological contribution of abnormal blood lipids to the development of coronary atherosclerosis is likely, as is well known from the general population [8]. Only recently, and after prolonged use in a large patient population, changes in body-fat distribution due to protease inhibitors have been recognized that were not reported in the original randomized trials [9,10]. More time will be needed to assess whether this new syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance [11] may bear a risk for a new, long-term morbidity due to coronary artery disease or other vascular complications. Protease inhibitors have dramatically improved the prognosis of HIV-infected patients and cannot be omitted from our therapeutic armamentarium at present. However, their use is not without potential risks and requires constant alertness of both the prescribing physician and the patient. Antiretroviral strategies that are highly active while being capable of partially or temporarily sparing protease inhibitors, such as combination treatments with non-nucleoside analogues or hydroxyurea [12,13], warrant further study.